The family of drugs based on N-[(1R)-1-cyclopropylethyl]-normorphine (1) hydrochloride (1.HCl), including various esters at the 6-O-position, has been shown to have high affinities for all three major opiate receptors, i.e., the mu, kappa, and delta receptors. See, e.g., U.S. Pat. No. 4,749,706 to Lawson. However, unlike all other reported opioids, 1 has relatively high efficacy for the kappa receptor and relatively low efficacy for the mu receptor. This unusual profile is demonstrated by several studies on 1 that show strong agonism for pain, modulated through the kappa receptors, but no mu agonism. Thus, 1 has low abuse potential. Remarkably, 1 is also free of punishing kappa agonism effects as well. In studies with rhesus monkeys, 1 has been shown to have a very weak cue for codeine in some concentrations and saline in higher concentration. A unique balance of activities between mu- and kappa-mediated effects that results in a drug without respiratory depression and free of gut transport side effects is also seen. See U.S. Pat. No. 4,749,706 to Lawson; U.S. Pat. No. 4,269,843 to DeGraw et al.; U.S. Pat. No. 4,218,454 to DeGraw et al.; Lawson et al. (1987) Proceedings of the 48th Meeting of the Committee of Problems in Drug Dependence, NIDA Research Monograph 76:309; Coop (2000), and Aceto et al. (2000) in Problems of Dependence: Proceedings of the 62nd Annual Scientific Meeting, the College on Problems of Drug Dependence, inc., NIDA Research Monograph 181, pp. 109-122, NIDA Publication No. 01-4918, L. S. Harris (Ed).
Addiction to alcohol, cocaine, heroin, and other commonly prescribed pain killers (such as oxycodone, hydrocodone, and the like) continues to be one of the most significant medical, social, and economic problems facing society. These drugs of abuse can induce significant neurochemical and neurophysiological alterations in the brain at cellular and molecular levels, and, in the setting of repeated self-exposure, which can lead to addiction, these changes may be persistent or even permanent. Such altered molecular, cellular, and neurophysiological “set points” in the brain, in turn, contribute to alterations in behavior—with implications for the specific addictive diseases (Kreek (2001) Ann. N.Y. Acad. Sci. 937:27-49). Specifically, it has been hypothesized that the endogenous opioid system (EOS), which regulates pleasure and reward in the brain under normal and drug-induced states, is involved in each of the major addictions (Kreek, 2001; Unterwald (2001) Ann. N.Y. Acad. Sci. 937:74-92). The EOS consists of various brain structures, cells, cell receptors, and endogenous peptide ligands for these receptors. The brain contains at least four different sets of opioid receptors and their associated peptide ligands. The four types of opioid receptors are known as the mu, kappa, delta, and sigma receptors.
The reinforcing effects of drugs of abuse, generally referred to as “euphoric” effects, lead to craving and make a human being or animal work to obtain drugs for self-administration. The primary sites of action for euphoria-inducing drugs are located in regions of the brain that have abundant dopaminergic terminals, specifically the mesolimbic-mesocortical dopaminergic system and especially the nucleus acumbens, the amygdala, and the anterior cingulate. In addition, the dorsal striatum, which has dopaminergic terminals associated with substantia nigra neurons, is also involved in some components of the behaviors of addiction. Dopamine does not work alone in those areas. Serotonin and other neurotransmitters, as well as neuropeptides, including those of the endogenous opioid system, are also active in these areas.
Dopaminergic neurons of the substantia nigra have projections that release dopamine in the caudate putamen, where there is a close linkage with the opioid system, including both peptides and receptors (Kreek, 2001). Dopaminergic neurons in the ventral tegmental area project to the mesolimbic-mesocortical dopaminergic system, with dopamine release in the nucleus acumbens, amygdala, anterior cingulate, and related regions—again with close connections to the endogenous opioid system.
Importantly, using quantitative techniques, several groups (Branch et al. (1992) Mol. Brain. Res. 14:231-238; Spangler et al. (1993) Mol. Brain Res. 19:323-7) have mapped the levels of opioid peptide gene expression and found abundant expression of mu- and kappa-acting peptides in the caudate putamen and the nucleus acumbens. Additional studies (Unterwald et al. (1994) Neuroreport 15:1613-6; Spangler et al. (1996) Mol. Brain Res. 38:71-6; Yuferov et al. (1999) Brain Res. Bull. 48:109-12) have found that mu, kappa, and delta receptors are abundantly expressed in the very regions where there are abundant dopaminergic terminal fields.
Opiates: Opiates such as heroin and its chief metabolite, morphine, act initially and specifically at the mu opioid receptor. Heroin and morphine also affect the dopaminergic system by inhibiting GABAergic neurons, which provide the normal inhibitory tone directly modulating dopaminergic neurons in the ventral tegmental area. This inhibition of GABAergic neurons results in increased dopamine release in the nucleus acumbens, amygdala, anterior cingulate, and other parts of the mesolimbic-mesocortical dopaminergic system. Thus, there is a very tight neurochemical connection between the endogenous opioid system and the dopamingergic system mediating the euphoric effects of opiates.
In one model that mimics the most common pattern of opiate abuse, in which morphine is administered in an intermittent, regularly spaced pattern, one group (Wang et al. (1999) Mol. Brain Res. 66:184-187) found that both dynorphin and kappa receptor gene expressions were enhanced in whole brains minus the cerebellum. These results suggest a close link between the kappa opioid system and the development of substance dependence to morphine.
Cocaine: Cocaine, in contrast, acts primarily at monoaminergic transporters—the dopamine transporter, the serotonin transporter, and the norepinephrine transporter—to block the normal presynaptic reuptake of neurotransmitters, thus yielding excessive neurotransmitter levels in the perisynaptic region. However, many studies have shown that cocaine significantly alters the endogenous opioid system, too (for review, see Kreek, 2001, cited supra).
A number of animal studies have investigated whether chronic cocaine exposure results in persistent alterations in the endogenous opioid system. Compelling evidence (reviewed in Unterwald et al. 2001, and Kreek, 2001, both cited supra) points to the importance of the mu and kappa opioid receptors in cocaine addiction and craving:
1. Yuferov et al. (1999), supra, showed that binge-pattern cocaine administration significantly alters mRNA levels for the mu opioid receptor in three brain regions only, all of which are linked to mesolimbic-mesocortical dopaminergic outflow—the nucleus acumbens, amygdala, and prefrontal cortex.
2. Unterwald et al. (1992) Brain Res. 584:314-8 has shown that mu receptor density is significantly increased in the anterior cingulate, caudate putamen, nucleus acumbens, and basolateral amygdala after 14 days of binge-pattern cocaine administration.
3. Unterwald et al. (1994), supra, has shown that 14 days of binge-pattern cocaine administration selectively increases the density of kappa opioid receptors, but again only in those dopaminergic fields of the nigrostriatal and mesolimbic-mesocortical dopaminergic systems.
4. Kuzminet al. (2000) Eur. Neuropsychopharmacol. 10:447-54 demonstrated that multiple opioid receptor systems (i.e., mu and kappa) play a role in reinforcing the properties of cocaine, and that cooperative interaction between mu- and kappa-opioid systems may be important during the initiation of cocaine self-administration.
5. An early study (Mello et al. (1993) Harv. Rev. Psychiatry 1: 168-83) has shown that buprenorphine, an opioid with mixed mu agonist/kappa antagonist character, significantly reduces both opiate and cocaine abuse in patients who had abused these drugs for more than ten years.
6. Two studies using either a chronic 14-day binge-pattern cocaine administration model (Spangler et al., 1993, supra) or a cocaine self-administration model (Daunais et al. (1993) Neuroreport 4:543-6) have shown increased gene expression of dynorphin—an endogenous opioid peptide with activity at kappa opioid receptors—in the caudate putamen. Other studies (Yuferov et al., 1999, supra) have shown that acute, subacute, and chronic cocaine administration enhances dynorphin gene expression.
Alcohol: Alcohol has also been shown to possibly alter both neurotransmitter and neuropeptide systems, including the dopaminergic and the endogenous opioid systems (for review, see Kreek, 2001).
Owing to the native role of the endogenous opioid system in pleasure and reward responses and to its alterations in chemical dependency and addiction, a number of opiates have been used with some success to treat addictions to opiates and/or alcohol. For example, it is known from many studies that heroin addiction in animals and humans may be satisfactorily treated with opioid drugs, specifically mu antagonists (e.g., naltrexone and nalmefene), long-acting and low- or partial-efficacy mu agonists (e.g., methadone and buprenorphine), and selective kappa agonists) See, for example: Mello et al. (1982) J. Pharmacol. Exp. Ther. 223:30-9; Bickel et al. (1988) Clin. Pharmacol. Therapeut. 43:72-8; Johnson et al. (1992) Jour. Amer. Med. Assoc. 267:2750-5; Robinson et al. (1993) Drug Alcohol Depen. 33:81-6; Meandzija et al. (1994) in: N. S. Miller, Ed., The principles and practice of addictions in psychiatry (Section XII, Chapter 4, pp. 1-5)(Philadelphia, Pa.: W. B. Saunders Company); Strain (1994) Amer. Jour. Psychiat. 151:1025-30; Jaffeet al. (1995) Psychiat. Ann. 25: 369-75; Herman et al. (1996) paper presented at the American Academy of Child and Adolescent Psychiatry, Philadelphia, Pa.; O'Brien et al. (1996) The Lancet 347:237-40. Litten et al. (1997) in N. S. Miller, Ed., The principles and practice of addictions in psychiatry (pp. 532-567) (Philadelphia, Pa.: W. B. Saunders Company); and Litten et al. (1999) J. Substance Abuse Treat 16:105-12. The latter reference also describes the successful use of naltrexone, a general opiate antagonist, for the treatment of alcoholism.
Currently, no pharmacotherapies are commercially available for cocaine addiction (see Litten et al., 1999). A number of different drugs are in development for this purpose, including buprenorphine, an opiate. However, a number of experimental studies have demonstrated that other opiates, particularly kappa-agonists, are effective in blocking cocaine-dependent responses such as drug preference and discrimination, self-administration, scheduled-controlled responding, and cocaine-induced hypersensitivity in animals. See Spealman et al. (1992) J. Pharmacol. Exp. Ther. 261:607-15; Spealman et al. (I 994) Behav. Pharmacol. 5:21-31; Suzuki et al. (1992) Jpn. J. Pharmacol. 58:435-42; Ukai et al. (1994) Yakubutsu Seishin Kodo 14:153-9; Crawford et al. (1995) Psychopharmacol. 120:392-9; Shippenerg et al. (1996) J. Pharmacol. Exp. Therap. 276:545-54; Negus et al. (1997) J. Pharm. Exper. Ther. 282(2):44-55; Mello et al. (1998) J. Pharm. Exper. Therap. 286(2):812-814; and Schenk et al. (1999) Psychopharmcol. 144:339-46.
These results suggest that activation of kappa opioid receptors may functionally antagonize some abuse-related effects of cocaine, possibly by inhibiting the release of dopamine from dopaminergic neurons.